Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis

A multicenter, randomized, double-blind, placebo-controlled phase II trial

Gideon M. Hirschfield, Olivier Chazouillères, Joost P. Drenth, Douglas Thorburn, Stephen A. Harrison, Charles S. Landis, Marlyn J Mayo, Andrew J. Muir, James F. Trotter, Diana J. Leeming, Morten A. Karsdal, Mark J. Jaros, Lei Ling, Kathline H. Kim, Stephen J. Rossi, Ransi M. Somaratne, Alex M. DePaoli, Ulrich Beuers

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. Methods: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. Results: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences −6.2 ng/ml (95% CI −10.7 to −1.7; p = 0.008) and −9.4 ng/ml (−14.0 to −4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. Conclusions: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. Lay summary: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Sclerosing Cholangitis
Placebos
Alkaline Phosphatase
Bile Acids and Salts
Fibrosis
Liver
Biomarkers
Complement C3
Intention to Treat Analysis
Cholangiography
Double-Blind Method
Liver Cirrhosis
Liver Diseases
Homeostasis
Hormones
Inflammation
Transplants
Biopsy
Safety
Survival

Keywords

  • Alkaline phosphatase
  • Collagen
  • Enhanced liver fibrosis
  • FGF19
  • Fibrogenesis
  • Pro-C3

ASJC Scopus subject areas

  • Hepatology

Cite this

Hirschfield, G. M., Chazouillères, O., Drenth, J. P., Thorburn, D., Harrison, S. A., Landis, C. S., ... Beuers, U. (Accepted/In press). Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.10.035

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis : A multicenter, randomized, double-blind, placebo-controlled phase II trial. / Hirschfield, Gideon M.; Chazouillères, Olivier; Drenth, Joost P.; Thorburn, Douglas; Harrison, Stephen A.; Landis, Charles S.; Mayo, Marlyn J; Muir, Andrew J.; Trotter, James F.; Leeming, Diana J.; Karsdal, Morten A.; Jaros, Mark J.; Ling, Lei; Kim, Kathline H.; Rossi, Stephen J.; Somaratne, Ransi M.; DePaoli, Alex M.; Beuers, Ulrich.

In: Journal of Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Hirschfield, GM, Chazouillères, O, Drenth, JP, Thorburn, D, Harrison, SA, Landis, CS, Mayo, MJ, Muir, AJ, Trotter, JF, Leeming, DJ, Karsdal, MA, Jaros, MJ, Ling, L, Kim, KH, Rossi, SJ, Somaratne, RM, DePaoli, AM & Beuers, U 2018, 'Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.10.035
Hirschfield, Gideon M. ; Chazouillères, Olivier ; Drenth, Joost P. ; Thorburn, Douglas ; Harrison, Stephen A. ; Landis, Charles S. ; Mayo, Marlyn J ; Muir, Andrew J. ; Trotter, James F. ; Leeming, Diana J. ; Karsdal, Morten A. ; Jaros, Mark J. ; Ling, Lei ; Kim, Kathline H. ; Rossi, Stephen J. ; Somaratne, Ransi M. ; DePaoli, Alex M. ; Beuers, Ulrich. / Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis : A multicenter, randomized, double-blind, placebo-controlled phase II trial. In: Journal of Hepatology. 2018.
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abstract = "Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. Methods: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. Results: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences −6.2 ng/ml (95{\%} CI −10.7 to −1.7; p = 0.008) and −9.4 ng/ml (−14.0 to −4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. Conclusions: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. Lay summary: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.",
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author = "Hirschfield, {Gideon M.} and Olivier Chazouill{\`e}res and Drenth, {Joost P.} and Douglas Thorburn and Harrison, {Stephen A.} and Landis, {Charles S.} and Mayo, {Marlyn J} and Muir, {Andrew J.} and Trotter, {James F.} and Leeming, {Diana J.} and Karsdal, {Morten A.} and Jaros, {Mark J.} and Lei Ling and Kim, {Kathline H.} and Rossi, {Stephen J.} and Somaratne, {Ransi M.} and DePaoli, {Alex M.} and Ulrich Beuers",
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TY - JOUR

T1 - Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis

T2 - A multicenter, randomized, double-blind, placebo-controlled phase II trial

AU - Hirschfield, Gideon M.

AU - Chazouillères, Olivier

AU - Drenth, Joost P.

AU - Thorburn, Douglas

AU - Harrison, Stephen A.

AU - Landis, Charles S.

AU - Mayo, Marlyn J

AU - Muir, Andrew J.

AU - Trotter, James F.

AU - Leeming, Diana J.

AU - Karsdal, Morten A.

AU - Jaros, Mark J.

AU - Ling, Lei

AU - Kim, Kathline H.

AU - Rossi, Stephen J.

AU - Somaratne, Ransi M.

AU - DePaoli, Alex M.

AU - Beuers, Ulrich

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. Methods: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. Results: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences −6.2 ng/ml (95% CI −10.7 to −1.7; p = 0.008) and −9.4 ng/ml (−14.0 to −4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. Conclusions: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. Lay summary: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

AB - Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. Methods: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. Results: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences −6.2 ng/ml (95% CI −10.7 to −1.7; p = 0.008) and −9.4 ng/ml (−14.0 to −4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. Conclusions: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. Lay summary: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

KW - Alkaline phosphatase

KW - Collagen

KW - Enhanced liver fibrosis

KW - FGF19

KW - Fibrogenesis

KW - Pro-C3

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